Fentanyl (N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide) is a potent synthetic opioid (μ receptor) agonist, related to pethidine, which possesses a fast onset and a moderate duration of action. The agonists useful in the present invention are chemical substances capable of combining with a receptor on a cell and initiating a reaction or activity that is characteristics of opiate narcotics, but which is not derived from opium.
Fentanyl, like other opioid agonists, interacts predominantly with μ binding sites in the brain, spinal cord and other tissues. Its principal pharmacological actions of therapeutic value are analgesia and sedation and, in this respect, fentanyl is approximately 100 times more potent than morphine and 7,500 times more potent than pethidine. It is therefore primarily used for its analgesic properties as a component of anesthesia and is normally administered by intravenous or intramuscular injection, although transdermal and transmucosal dosage forms have also been developed.
When administered by the intravenous route, the onset of activity is almost immediate and the duration of analgesia is about 30 to 60 minutes after a single dose of up to 0.1 mg. Following intramuscular administration of fentanyl, the onset of activity is 7 to 8 minutes with a duration of activity of 1 to 2 hours. Intravenous fentanyl may therefore be utilized for analgesic action of short duration during the anesthetic periods of premedication, induction and maintenance and in the immediate postoperative period (recovery room) as the need arises. It may also be used as a narcotic analgesic supplement in general or regional anesthesia and, with a neuroleptic agent such as droperidol, as an anesthetic premedication for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia. In selected high risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopaedic procedures, it may also be used as an anesthetic agent with oxygen.
Typical dosages for use as a premedication or postoperatively are 50 to 100 μg/kg of body weight. When used as an adjunct to general anesthesia, doses may range from 2 μg/kg to 20–50 μg/kg depending upon the complexity and duration of the operation.
Intravenously administered fentanyl tends to accumulate in skeletal muscle and fat from where it is slowly released into the blood. Repeated doses therefore lead to accumulation and prolonged activity. The plasma protein binding decreases with increasing ionization of the drug and alterations in pH may therefore affect the distribution of fentanyl between plasma and the central nervous system. Fentanyl is primarily transformed in the liver and a high first pass effect is therefore observed when the drug is administered by non-parenteral routes. However, about 75% of an intravenous dose of fentanyl is recovered in the urine with less than 10% as the unchanged drug, the main metabolites being norfentanyl and despropionylfentanyl which are both inactive.
In addition to analgesia, fentanyl may cause alterations in mood, euphoria, dysphoria and drowsiness. Moreover, therapeutic levels of fentanyl may cause nausea and vomiting directly by stimulation of the chemoreceptor trigger zone. However, nausea and vomiting are significantly more common in ambulatory than in recumbent patients.
One of the most serious adverse effects associated with use of intravenous fentanyl is hypoventilation. This is seen as a reduction in the respiratory rate (breaths per minute) and in the oxygen saturation level of the blood. Indeed, this hypoventilation may last longer than the analgesic effect. It is therefore necessary to ensure that an opioid antagonist, intubation equipment and oxygen are readily available when fentanyl is injected.
Fentanyl may also caus muscle rigidity, particularly in the muscles of respiration. This may occur in the postoperative period and patients should therefore be carefully monitored, especially those receiving a high dose of fentanyl. Should this effect occur, it may be reversed by administration of naloxone or overcome by neuromuscular-blocking drugs.
As with other opioid agonists, fentanyl increases the tone and decreases the propulsive contractions of the gastrointestinal tract leading to constipation. However, at therapeutic dosages, fentanyl exerts minimal effects on the cardiovascular system, although orthostatic hypotension and fainting may occur in some patients and vagally-mediated bradycardia has been reported.
The transdermal dosage form is available as a range of patches offering a range of release rates from 25 to 100 μg of fentanyl per hour over 3 days. In this dosage form, fentanyl is released as a free base. The actual amount released from the patch varies with time and also between patients. Essentially, the skin absorbs fentanyl and a depot of fentanyl concentrates in the upper skin layers. The serum fentanyl concentrations gradually increase until levelling off with peak serum concentrations being attained between 24 and 72 hours. After several sequential 72-hour applications, patients reach and maintain a steady state serum concentration. After removal of the patch, the serum fentanyl concentrations gradually decline with levels falling by 50% in about 17 hours. This slower elimination, as compared to that after intravenous administration, is due to continued absorption of drug from the depot in the skin after removal of the patch.
In view of the above, the transdermal patch is indicated for the management of chronic pain in patients who require continuous opioid analgesia for pain that cannot be managed by paracetamol-opioid combinations, non-steroidal analgesics or PRN dosing with short acting opioids. It is not indicated for the management of acute or postoperative pain because of the risk of hypoventilation (4% incidence) and should not be administered to children under 12 unless used in an authorized research setting.
The oral transmucosal system consists of a lozenge of fentanyl citrate attached to a handle. The lozenge is sucked until complete dissolution is achieved (normally within about 12 to 15 minutes). A bioavailability study of this device in comparison with intravenous and oral solution administration showed that the absolute bioavailability from the device was 51%, as compared to 32% from the oral solution, and that the tmax was also faster from the device. It is estimated that about 75% of the total dose from the device is swallowed and a third of this amount reaches the systemic circulation in addition to the 25% of the dose which is absorbed sublingually.
The oral transmucosal device has been approved for use for anesthetic premedication in children and adults and for use in anesthesia or monitored anesthesia care. The approved dose for this dosage form for premedication is between 5–15 μg/kg (400 μg) for adults. However, this product is only authorized for administration in hospital settings where there is immediate access to life support equipment, including oxygen, facilities for endotracheal intubation, intravenous fluids and opioid antagonists. Also, there is a restriction on personnel authorized to administer this product.
This device is clearly unsuitable for use during and after operations and can therefore only be used for some of the indications for which the intravenous injection form can be used. Also, although several clinical trials have shown that the oral transmucosal device is generally useful as a premedicant in children prior to surgery, there is a high incidence of adverse effects, some of which could complicate the induction of anesthesia.
The main adverse effect is mild facial pruritus (incidence of about 50 to 60%) but the occurrence of nausea and vomiting has also been high (30 to 50%). Indeed, the high incidence of vomiting in one study in children led to the termination of the study and is probably the most troublesome side-effect. Moreover, pre-treatment with an anti-emetic has not proved to be effective in decreasing the incidence of nausea and vomiting. In addition, the device has also been shown to reduce oxygen saturation levels in blood in some children, thus necessitating constant blood oxygen monitoring in patients taking the product. There are thus significant drawbacks with respect to the adverse event profile which may limit the clinical usefulness of the oral transmucosal device form of fentanyl in some settings as a premedication before surgery.
Approval has been sought for the use of the transmucosal device in the treatment of breakthrough pain in chronic pain patients already receiving opioid therapy in home or hospital settings. The regulatory authorities have expressed concern regarding the incorporation of a potent and narcotic drug into a device, which looks like a child's confectionery product. It is feared that the lollipop form of the product would be attractive to a child, and result in accidental consumption of the narcotic, with potential life-threatening consequences.
It is clear from the above that it would be highly desirable from a clinical point of view to find a way of administering fentanyl and other opioid (μ receptor) agonists which is easy for the patient to accomplish and which bypasses first pass metabolism in the liver while still providing good bioavailability of the active ingredient and a rapid onset of activity.
According to the present invention there is therefore provided a pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, an opioid (μ receptor) agonist, characterized in that the composition is in the form of a fast-dispersing dosage form designed to release the active ingredient rapidly in the oral cavity.
It has been found that such fast-dispersing dosage forms promote pre-gastric absorption of the active ingredient, that is, absorption of the active ingredient from that part of the alimentary canal prior to the stomach. The term “pre-gastric absorption” thus includes buccal, sublingual, oropharyngeal and oesophageal absorption. An opioid (μ receptor) agonist, such as fentanyl, absorbed by such pre-gastric absorption, passes straight into the systemic circulatory system thereby avoiding first pass metabolism in the liver. Accordingly, bioavailability of an opioid (μ receptor) agonist, such as fentanyl, absorbed in this way may also be increased. This means that the dose of fentanyl or other opioid (μ receptor) agonist may be reduced while still producing the desired beneficial effects and this decrease in dose will result in a corresponding reduction of unwanted side effects.
One example of a fast-dispersing dosage form is described in U.S. Pat. No. 4,855,326 in which a melt spinnable carrier agent, such as sugar, is combined with an active ingredient and the resulting mixture spun into a “candy-floss” preparation. The spun “candy-floss” product is then compressed into a rapidly dispersing, highly porous solid dosage form.
U.S. Pat. No. 5,120,549 discloses a fast-dispersing matrix system which is prepared by first solidifying a matrix-forming system dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix-forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fast-dispersing matrix.
U.S. Pat. No. 5,079,018 discloses a fast-dispersing dosage form which comprises a porous skeletal structure of a water soluble, hydratable gel or foam forming material that has been hydrated with water, rigidified in the hydrated state with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0° C. or below to leave spaces in place of hydration liquid.
Published International Application No. WO 93/12769 (PCT/JP93/01631) describes fast-dispersing dosage forms of very low density formed by gelling, with agar, aqueous systems containing the matrix-forming elements and active ingredient, and then removing water by forced air or vacuum drying.
U.S. Pat. No. 5,298,261 discloses fast-dispersing dosage forms which comprise a partially collapsed matrix network that has been vacuum-dried above the collapse temperature of the matrix. However, the matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.
Published International Application No. WO 91/04757 (PCT/US90/05206) discloses fast-dispersing dosage forms which contain an effervescent disintegration agent designed to effervesce on contact with saliva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavity.
EP-A-0627218 discloses a fast-dispersing dosage form which comprises a tablet comprising a sugar alcohol or the like as principal ingredient which is prepared by the wet granulation method in which a kneaded mixture of the sugar alcohol or the like with a drug is compression molded before drying.
Published International Application No. WO 94/14422 describes a process for drying frozen discrete units in which the solvent is removed under conditions whereby the solvent is evaporated from the solid through the liquid phase to a gas, rather than subliming from a solid to a gas as in lyophilization. This is achieved by vacuum drying at a temperature below the equilibrium freezing point of the composition at which point the solvent (such as water) changes phase.